Efficient cancer modeling through CRISPR-Cas9/HDR-based somatic precision gene editing in mice

CRISPR-Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR-Cas9 vector system that now allows homology...

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Bibliographic Details
Published in:Science advances 2023-05, Vol.9 (19), p.eade0059
Main Authors: Bu, Wen, Creighton, Chad J, Heavener, Kelsey S, Gutierrez, Carolina, Dou, Yongchao, Ku, Amy T, Zhang, Yiqun, Jiang, Weiyu, Urrutia, Jazmin, Jiang, Wen, Yue, Fei, Jia, Luyu, Ibrahim, Ahmed Atef, Zhang, Bing, Huang, Shixia, Li, Yi
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Cancer
CRISPR-Cas Systems - genetics
Disease Models, Animal
Gene Editing - methods
Humans
Mice
Neoplasms - genetics
Neoplasms - therapy
Recombinational DNA Repair
Research Methods
SciAdv r-articles
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Summary:CRISPR-Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR-Cas9 vector system that now allows homology-directed repair-mediated precise editing of any proto-oncogene in murine somatic tissues to generate tumor models with high flexibility and efficiency. Somatic editing of either or in both normal and hyperplastic mammary glands led to swift tumorigenesis. The resulting tumors shared some histological, transcriptome, and proteome features with tumors induced by lentivirus-mediated expression of the respective oncogenes, but they also exhibited some distinct characteristics, particularly showing less intertumor variation, thus potentially offering more consistent models for cancer studies and therapeutic development. Therefore, this technological advance fills a critical gap between the power of CRISPR technology and high-fidelity mouse models for studying human tumor evolution and preclinical drug testing.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ade0059